Overall Program Project Summary/Abstract: In this Program Project Grant (PPG), we have been testing the hypothesis that systemic and cerebral vascular disease (even at a subclinical level) modulates the onset of the cognitive syndrome of Alzheimer?s disease (AD). We reported that A? deposition is linked to brain structure, markers of cholesterol transport and inflammation. Taken in combination, hippocampal atrophy, white matter lesions, and the extent of A? deposition provided powerful prediction of dementia after two years of follow-up. However, although half of cognitively normal subjects age 85+ were found to have A? deposition, two-thirds of these ?A?-positive? subjects showed no clinical progression over two years. Conversely, one-third of the cognitively normal subjects who progressed to an AD syndrome over two years were ?A?-negative?. These new findings indicate that vascular disease may act as: 1) as a moderating factor that alters brain compensation for AD pathology; 2) as a contributor to AD pathology; or 3) both. The implications of these are critically different and impact our understanding of the pathophysiology of dementia in old age, and by extension, its preventive treatments. The goal of this PPG is to gain further insight into the pre-symptomatic (or subclinical) dynamic processes of the two most common pathologies in old age, vascular disease and AD, in relationship to cognition. In order to longitudinally examine this dynamic process, we have assembled two cohorts: 1) the GEMS cohort of the very elderly (~90 yrs) where the incidence of cognitive syndromes is very high and 2) the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) cohort that is younger (65- 75 yrs) and where the expected incidence of cognitive syndromes is much lower. The value of extending our observations of the GEMS cohort through this late stage of frequent clinical change and coupling this to a postmortem study is clear. The importance of the Heart SCORE cohort is that it allows us to see changes at the subclinical level. If we observe an association between vascular disease, AD pathology, and cognitive decline in the Heart SCORE cohort, it will support the hypotheses generated from the GEMS cohort. This design allows us to gather in-depth information on the association between vascular disease, AD pathology and cognition within a 5-year period that would otherwise take more than a decade. The studies in the GEMS cohort (Project-1) and the Heart SCORE cohort (Project-2) are enriched by coupling them to the neuropathological evaluations of Project-3 and the pharmacokinetic study of the newly applied tau positron emission tomography (PET) technology (Project-4) that aims to simultaneously add missing components to the characterization of tau-PET and improve the accuracy and value of the tau-PET data acquired by the field in general. New Project 5 further aims to increase the quantitative value of all PPG PET data by evaluating several methods of partial volume correction and point spread function recovery reconstructions validated with realistic 3D-printed brain phantoms based on human MRI scans.